Search

Hannah E O’Farrell, Rayleen V Bowman, Kwun M Fong, Ian A Yang Faculty of Medicine, the University of Queensland, Brisbane, QLD, AustraliaCorrespondence: Hannah E O’Farrell, Faculty of Medicine, the University of Queensland, Brisbane, QLD, Australia, Tel +61 07 3139 4110, Email hannah.ofarrell@uq.net.auPurpose: Molecular biomarkers for chronic obstructive pulmonary disease (COPD) severity have been difficult to identify. We aimed to assess extracellular vesicle miRNAs’ potential as a blood biomarker in discriminating disease severity in participants with COPD.Patients and Methods: Plasma extracellular vesicles (EVs) were obtained from two COPD cohorts (n = 20 during an exacerbation event, n = 20 during stable state), with varying disease severity (GOLD stages). The miRCURY LNA miRNA Serum/Plasma assay, specific to 179 targets, was used to evaluate EV miRNA expression. The miRNAs that were significantly dysregulated were further assessed for discriminatory power using ROC curve analysis, as well as their role in relevant biological pathways.Results: One miRNA was significantly dysregulated between moderate GOLD participants compared to severe/very severe GOLD participants, with an AUC of 0.798, p = 0.01 for miR-374b-5p. Five miRNAs were significantly dysregulated between exacerbating and stable COPD participants, with miR-223-3p resulting in the highest AUC (0.755, p = 0.006) for a single miRNA, with a combination of three miRNAs (miR-92b-3p, miR-374a-5p and miR-106b-3p) providing the highest discriminatory power (AUC 0.820, p = 0.001). The “cytokine–cytokine receptor interaction” (hsa04060 pathway) was the most significant KEGG pathway enriched for three out of the five miRNAs associated with COPD exacerbations.Conclusion: This initial small-scale study suggests that the bioactive cargo (miRNAs) in plasma EVs holds specific biological information for the severity of airflow obstruction and COPD exacerbations, warranting further investigation.Keywords: COPD, exacerbations, extracellular vesicles, miRNAs

Lung cancer screening can reduce the mortality of lung cancer, the leading cause of cancer death worldwide. Real world screening experience highlights areas for improvement in a complex and changing world, particularly ethnic disparity, and the potential for new and emerging risk factors, in addition to well known risk of smoking and asbestos exposure. Biomarkers offer the promise of objective risk assessment but are not yet ready for clinical practice. This review discusses some of the major issues faced by lung cancer screening and the potential role for biomarkers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Lung cancer is the most common type of cancer. Detection of lung cancer at an early stage can reduce mortality rates. Pulmonary nodules may represent early cancer and can be identified through computed tomography (CT) scans. Malignant risk can be estimated based on attributes like size, shape, location, and density., Purpose: Deep learning algorithms have achieved remarkable advancements in this domain compared to traditional machine learning methods. Nevertheless, many existing anchor-based deep learning algorithms exhibit sensitivity to predefined anchor-box configurations, necessitating manual adjustments to obtain optimal outcomes. Conversely, current anchor-free deep learning-based nodule detection methods normally adopt fixed-size nodule models like cubes or spheres., Methods: To address these technical challenges, we propose a multiscale 3D anchor-free deep learning network (M3N) for pulmonary nodule detection, leveraging adjustable nodule modeling (ANM). Within this framework, ANM empowers the representation of target objects in an anisotropic manner, with a novel point selection strategy (PSS) devised to accelerate the learning process of anisotropic representation. We further incorporate a composite loss function that combines the conventional L2 loss and cosine similarity loss, facilitating M3N to learn nodules' intensity distribution in three dimensions., Results: Experiment results show that the M3N achieves 90.6% competitive performance metrics (CPM) with seven predefined false positives per scan on the LUNA 16 dataset. This performance appears to exceed that of other state-of-the-art deep learning-based networks reported in their respective publications. Individual test results also demonstrate that M3N excels in providing more accurate, adaptive bounding boxes surrounding the contours of target nodules., Conclusions: The newly developed nodule detection system reduces reliance on prior knowledge, such as the general size of objects in the dataset, thus it should enhance overall robustness and versatility. Distinct from traditional nodule modeling techniques, the ANM approach aligns more closely with the morphological characteristics of nodules. Time consumption and detection results demonstrate promising efficiency and accuracy which should be validated in clinical settings., (© 2024 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background and Objectives: Coronary artery calcification (CAC) is a frequent additional finding on lung cancer screening (LCS) low-dose computed tomography (LDCT). Cardiovascular disease (CVD) is a major cause of death in LCS participants. We aimed to describe prevalence of incidental CAC detected on LDCT in LCS participants without prior history of coronary artery disease (CAD), evaluate their CVD risk and describe subsequent investigation and management., Methods: Prospective observational nested cohort study including all participants enrolled at a single Australian site of the International Lung Screen Trial. Baseline LDCTs were reviewed for CAC, and subsequent information collected regarding cardiovascular health. 5-year CVD risk was calculated using the AusCVD risk calculator., Results: 55% (226/408) of participants had CAC on LDCT and no prior history of CAD, including 23% with moderate-severe CAC. Mean age of participants with CAC was 65 years, 68% were male. 53% were currently smoking. Majority were high risk (51%) or intermediate risk (32%) of a cardiovascular event in 5 years. 21% of participants were re-stratified to a higher CVD risk group when CAC detected on LCS was incorporated. Only 10% of participants with CAC received lifestyle advice (only 3% currently smoking received smoking cessation advice). 80% of participants at high-risk did not meet guideline recommendations, with 47% of this group remaining without cholesterol lowering therapy., Conclusion: LCS with LDCT offers the potential to identify and communicate CVD risk in this population. This may improve health outcomes for high-risk LCS participants and further personalize management once screening results are known., (© 2024 The Author(s). Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background and Aims: HCC is the most common type of primary liver cancer and is a common malignancy worldwide. About half of all new liver cancers worldwide each year occur in China, including Hong Kong, due to a high prevalence of HBV infection. HBV DNA integrates into the human genome, disrupting the endogenous tumor suppressors/regulatory genes or enhancing the activity of proto-oncogenes. It would be useful to examine the different NGS-based databases to provide a more unbiased and comprehensive survey of HBV integration., Approach and Results: We aimed to take advantage of publicly available data sets of different regional cohorts to determine the disparity landscapes of integration events among sample cohorts, tissue types, chromosomal positions, individual host, and viral genes, as well as genic locations. By comparing HCC tumors with non tumorous livers, the landscape of HBV integration was delineated in gene-independent and gene-dependent manners. Moreover, we performed mechanistic investigations on how HBV-TERT integration led to TERT activation and derived a score to predict patients' prognostication according to their clonal disparity landscape of HBV integration., Conclusions: Our study uncovered the different levels of clonal enrichment of HBV integration and identified mechanistic insights and prognostic biomarkers. This strengthens our understanding of HBV-associated hepatocarcinogenesis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The WHO recently published a Tobacco Knowledge Summary (TKS) synthesizing current evidence on tobacco and COPD, aiming to raise awareness among a broad audience of health care professionals. Furthermore, it can be used as an advocacy tool in the fight for tobacco control and prevention of tobacco-related disease. This article builds on the evidence presented in the TKS, with a greater level of detail intended for a lung-specialist audience. Pulmonologists have a vital role to play in advocating for the health of their patients and the wider population by sharing five key messages: (1) Smoking is the leading cause of COPD in high-income countries, contributing to approximately 70% of cases. Quitting tobacco is an essential step toward better lung health. (2) People with COPD face a significantly higher risk of developing lung cancer. Smoking cessation is a powerful measure to reduce cancer risk. (3) Cardiovascular disease, lung cancer and type-2 diabetes are common comorbidities in people with COPD. Quitting smoking not only improves COPD management, but also reduces the risk of developing these coexisting conditions. (4) Tobacco smoke also significantly impacts children's lung growth and development, increasing the risk of respiratory infections, asthma and up to ten other conditions, and COPD later in life. Governments should implement effective tobacco control measures to protect vulnerable populations. (5) The tobacco industry's aggressive strategies in the marketing of nicotine delivery systems and all tobacco products specifically target children, adolescents, and young adults. Protecting our youth from these harmful tactics is a top priority., (© 2024. The Author(s).)

Introduction: The TNM classification of lung cancer is periodically revised. The International Association for the Study of Lung Cancer collected and analyzed a new database to inform the forthcoming ninth edition of the TNM classification. The results are herewith presented., Methods: After exclusions, 76,518 patients from a total of 124,581 registered patients were available for analyses: 58,193 with clinical stage, 39,192 with pathologic stage, and 62,611 with best stage NSCLC. The proposed new N2 subcategories (N2a, involvement of single ipsilateral mediastinal or subcarinal nodal station, and N2b, involvement of multiple ipsilateral mediastinal nodal stations with or without involvement of the subcarinal nodal station) and the new M1c subcategories (M1c1, multiple extrathoracic metastases in one organ system, and M1c2, multiple extrathoracic metastases in multiple organ systems) were considered in the survival analyses. Several potential stage groupings were evaluated, using multiple analyses, including recursive partitioning, assessment of homogeneity within and discrimination between potential groups, clinical and statistical significance of survival differences, multivariable regression, and broad assessment of generalizability., Results: T1N1, T1N2a, and T3N2a subgroups are assigned to IIA, IIB, and IIIA stage groups, respectively. T2aN2b and T2bN2b subgroups are assigned to IIIB. M1c1 and M1c2 remain in stage group IVB. Analyses reveal consistent ordering, discrimination of prognosis, and broad generalizability of the proposed ninth edition stage classification of lung cancer., Conclusions: The proposed stages for the ninth edition TNM improve the granularity of nomenclature about anatomic extent that has benefits as treatment approaches become increasingly differentiated and complex., Competing Interests: Disclosure Dr. Nishimura and Ms. Giroux report that statistical consulting by Cancer Research And Biostatistics (CRAB) employees for data collection, analysis, and manuscript preparation in the Staging Project is funded by the International Association for the Study of Lung Cancer (IASLC). Dr. Fong reports payments made to his institution by Competitive Research Grant, MRFF EPCDR Improving Diagnosis in Cancers Low Survival Rates; Competitive Research Grant, NHMRC Ideas grant: Early lung cancer biomarkers; Competitive Research Grant, MRFF Next Generation Clinical Researchers Program - Practitioner Fellowship; Competitive Research Grant, NHMRC Project: Novel biomarkers for lung cancer; Competitive Research Grant, NHMRC Low dose computed tomography (LDCT) to diagnose lung cancer; payments to himself by UpToDate Reviewer and Cochrane Clinical Answers Reviewer; payment for travel support to WCLC, ATS in 2022 and PCCP in 2023; payments for travel support by the 2023 Asia Pacific Coalition Against Lung Cancer; and payments from the Asia Pacific Society of Respirology former President and EXCO member; support with loan bronchoscopes for the purpose of a research study—no financial funding from Olympus; and software licensing for Computer Aided Diagnosis research in the International Lung Screen Trial (ILST) from Mevis Veolity. Dr. Giuliani reports receiving payments for Advisory Board member from AstraZeneca and Bristol Myers Squibb; and being Section Editor, of the International Journal of Radiation Oncology, Biology and Physics. Dr. Marom reports receiving honorarium for lectures from Boehringer Ingelheim, Merck Sharp & Dohme, and AstraZeneca. Dr. Nicholson reports receiving personal fees from Merck, Boehringer Ingelheim, Novartis, AstraZeneca, Bristol-Myers Squibb, Roche, AbbVie, Oncologica, UpToDate, the European Society of Oncology, and Liberum; and grants and personal fees from Pfizer, outside of the submitted work. Dr. Van Schil reports receiving lecture and consulting institutional fees from AstraZeneca and Janssen and lecture and consulting personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, and Roche; and having leadership positions in BACTS (Belgian Association for Cardiothoracic Surgery) as treasurer and IASLC (International Association for the Study of Lung Cancer) as president with no fees. Dr. Travis reports receiving a grant from the National Cancer Institute: MSKCC Core Grant: P30 CA008748. Dr. Rusch reports receiving support for the present manuscript from NIH Cancer Support Grant P30-CA008748; institutional funding for a clinical trail from Genentech; and miscellaneous honoraria for lectures of no commercial interest at various universities; funding for meeting preparation and attendance by NIH Thoracic Malignancy Steering Committee (Co-Chair); and reports being a committee member of MARS II and RAMON trials (Cancer Research UK). Dr. Asamura reports receiving funding for analyses of results and manuscript preparation and support from the IASLC for attending meetings. The remaining authors report no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Necrotizing fasciitis (NF) is a rare but potentially life-threatening soft tissue infection. The objective of this study was to assess the association between timely surgery within 6 h and hospital mortality in patients with limb NF, and to describe the trends in patients with NF, time to surgery and standardized mortality ratio (SMR) over 11 years., Methods: This was a multicenter, retrospective cohort study of all intensive care unit patients who had emergency surgery within 24 h of hospitalization for limb NF between April 1, 2008 and March 31, 2019 in Hong Kong. Timely surgery was defined as the first surgical treatment within 6 h of initial hospitalization. Appropriate antibiotics were achieved if the patient was given antibiotic(s) for all documented pathogens prior to or on day of culture results. The primary outcome was hospital mortality., Results: There were 495 patients (median age 62 years, 349 (70.5%) males) with limb NF treated by surgery within 24 h of hospitalization over the 11 years. Appropriate antibiotic(s) were used in 392 (79.2%) patients. There were 181 (36.5%) deaths. Timely surgery was not associated with hospital mortality (Relative Risk 0.89, 95% CI: 0.73 to 1.07) but admission year, advanced age, higher severity of illness, comorbidities, renal replacement therapy, vasopressor use, and type of surgery were significant predictors in the multivariable model. There was an upward trend in NF diagnosis (1.9 cases/year, 95% CI: 0.7 to 3.1; P < 0.01; R 2  = 0.60) but there was no downward trend in median time to surgery (-0.2 h/year, 95% CI: -0.4 to 0.1; P = 0.16) or SMR (-0.02/year, 95% CI: -0.06 to 0.01; P = 0.22; R 2  = 0.16)., Conclusions: Among patients operated within 24 h, very early surgery within 6-12 h was not associated with survival. Increasing limb NF cases were reported each year but mortality remained high despite a high rate of appropriate antibiotic use and timely surgical intervention., (© 2024. The Author(s).)

Objective: Fat mass and obesity-associated protein (FTO), an eraser of N 6 -methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown., Design: The functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment., Results: FTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumour-infiltrating CD8 + T cells. Furthermore, we identified GPNMB to be a downstream target of FTO, which reduced the m6A abundance of GPNMB, hence, stabilising it from degradation by YTH N 6 -methyladenosine RNA binding protein F2. Of note, GPNMB was packaged into sEVs derived from HCC cells and bound to the surface receptor SDC4 of CD8 + T cells, resulting in the inhibition of CD8 + T cell activation. A potential FTO inhibitor, CS2, suppresses the oncogenic functions of HCC cells and enhances the sensitivity of anti-PD-1 and sorafenib treatment., Conclusion: Targeting the FTO/m6A/GPNMB axis could significantly suppress tumour growth and metastasis, and enhance immune activation, highlighting the potential of targeting FTO signalling with effective inhibitors for HCC therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This study analyzed all metastatic categories of the current TNM classification of NSCLC to propose modifications of the M component in the next edition (ninth) of the classification., Methods: A database of 124,581 patients diagnosed between 2011 and 2019 was established; of these, 14,937 with NSCLC in stages IVA to IVB were available for this analysis. Overall survival was calculated using the Kaplan-Meier method, and prognosis was assessed using multivariable-adjusted Cox proportional hazards regression., Results: The eighth edition M categories revealed good discrimination in the ninth edition data set. Assessments revealed that an increasing number of metastatic lesions were associated with decreasing prognosis; because this seems to be a continuum and adjustment for confounders was not possible, no specific lesion number was deemed appropriate for stage classification. Among tumors involving multiple metastases, decreasing prognosis was found with an increasing number of organ systems involved. Multiple assessments, including after adjustment for potential confounders, revealed that M1c patients who had metastases to a single extrathoracic organ system were prognostically distinct from M1c patients who had involvement of multiple extrathoracic organ systems., Conclusions: These data validate the eighth edition M1a and M1b categories, which are recommended to be maintained. We propose the M1c category be divided into M1c1 (involvement of a single extrathoracic organ system) and M1c2 (involvement of multiple extrathoracic organ systems)., Competing Interests: Disclosure Dr. Fong reports receiving grants and contracts from MRFF EPCDR, NHMRC Ideas Grant, MRFF Next Generation Clinical Researchers Program, NHMRC; receiving funds from UpToDate as reviewer and Cochrane Clinical Answers as reviewer; and receiving equipment support from Olympus and Mevis Veolity. Mr. Rosenthal reports receiving fees for service from IASLC to complete work associated with publication. Ms. Giroux reports receiving fees for service from IASLC to complete work associated with publication. Dr. Nishimura reports receiving fees for service from IASLC to complete work associated with publication. Dr. Erasmus reports receiving honoraria from Canadian Association of Radiologists. Dr. Lievens reports receiving grants and contracts for the ImmunoSABR EU Project, HERO-VBHC chair; consulting fees from AstraZeneca; and honoraria from Merck Sharp & Dohme. Dr. Marom reports receiving honoraria from Boehringer Ingelheim, Merck, and AstraZeneca. Dr. Putora reports receiving grants or contracts from Bayer, Takeda, and AstraZeneca. Dr. Suárez reports receiving consulting fees from AstraZeneca and Roche; honoraria from AstraZeneca. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear., Design: Using an in vivo mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation., Results: FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes., Conclusion: The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: HCC is an aggressive cancer with a poor clinical outcome. Understanding the mechanisms that drive tumor initiation is important for improving treatment strategy. This study aimed to identify functional cell membrane proteins that promote HCC tumor initiation., Approach and Results: Tailor-made siRNA library screening was performed for all membrane protein-encoding genes that are upregulated in human HCC (n = 134), with sphere formation as a surrogate readout for tumor initiation. Upon confirmation of membranous localization by immunofluorescence and tumor initiation ability by limiting dilution assay in vivo, LanC-like protein-1 (LANCL1) was selected for further characterization. LANCL1 suppressed intracellular reactive oxygen species (ROS) and promoted tumorigenicity both in vitro and in vivo. Mechanistically, with mass spectrometry, FAM49B was identified as a downstream binding partner of LANCL1. LANCL1 stabilized FAM49B by blocking the interaction of FAM49B with the specific E3 ubiquitin ligase TRIM21, thus protecting FAM49B from ubiquitin-proteasome degradation. The LANCL1-FAM49B axis suppressed the Rac1-NADPH oxidase-driven ROS production, but this suppression of ROS was independent of the glutathione transferase function of LANCL1. Clinically, HCCs with high co-expression of LANCL1 and FAM49B were associated with more advanced tumor stage, poorer overall survival, and disease-free survival. In addition, anti-LANCL1 antibodies targeting the extracellular N-terminal domain were able to suppress the self-renewal ability, as demonstrated by the sphere formation ability of HCC cells., Conclusions: Our data showed that LANCL1 is a cell surface protein and a key contributor to HCC initiation. Targeting the LANCL1-FAM49B-Rac1-NADPH oxidase-ROS signaling axis may be a promising therapeutic strategy for HCC., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2023-5/coif). K.M.F. serves as an unpaid editorial board member of Translational Lung Cancer Research from August 2023 to July 2025. K.M.F. has received competitive Research Grant Funding from MRFF and NHMRC in the past 36 months, honoraria or royalties from UpToDate and Cochrane Clinical Answers, travel support funding from WCLC, ATS, and PCCP; and in-kind equipment funding from Olympus and Mevis Veolity. K.M.F. is the Former President of the Asia Pacific Society of Respirology. The other authors have no conflicts of interest to declare.

Background: Evaluation of psychosocial consequences of lung cancer screening with LDCT in high-risk populations has generally been performed using generic psychometric instruments. Such generic instruments have low coverage and low power to detect screening impacts. This study aims to validate an established lung cancer screening-specific questionnaire, Consequences Of Screening Lung Cancer (COS-LC), in Australian-English and describe early results from the baseline LDCT round of the International Lung Screen Trial (ILST)., Methods: The Danish-version COS-LC was translated to Australian-English using the double panel method and field tested in Australian-ILST participants to examine content validity. A random sample of 200 participants were used to assess construct validity using Rasch item response theory models. Reliability was assessed using classical test theory. The COS-LC was administered to ILST participants at prespecified timepoints including at enrolment, dependent of screening results., Results: Minor linguistic alterations were made after initial translation of COS-LC to English. The COS-LC demonstrated good content validity and adequate construct validity using psychometric analysis. The four core scales fit the Rasch model, with only minor issues in five non-core scales which resolved with modification. 1129 Australian-ILST participants were included in the analysis, with minimal psychosocial impact observed shortly after baseline LDCT results., Conclusion: COS-LC is the first lung cancer screening-specific questionnaire to be validated in Australia and has demonstrated excellent psychometric properties. Early results did not demonstrate significant psychosocial impacts of screening. Longer-term follow-up is awaited and will be particularly pertinent given the announcement of an Australian National Lung Cancer Screening Program., Trial Registration: NCT02871856., (© 2024. The Author(s).)

Introduction: Physical activity (PA) is a potentially modifiable risk factor for lung cancer, with previous research revealing that people who engage in more PA have lower risk of developing lung cancer. PA levels of lung cancer screening participants have not previously been explored., Methods: Participants at a single Australian International Lung Screen Trial site were eligible for assessment of self-reported PA levels (International Physical Activity Questionnaire and Physical Activity Scale for the Elderly) and physical assessments (6-min walk distance, hand grip muscle strength, daily step count, and body composition) at a single time point during lung cancer screening. Statistics were predominantly descriptive, with parametric data presented as mean and SD and nonparametric data presented as median and interquartile range (IQR)., Results: A total of 178 participants were enrolled in this study, with a median age of 61 years. Of the participants, 61% were men and 51% were people who currently smoke. The median total International Physical Activity Questionnaire score was 1756 MET/min/wk (IQR 689, 4049). Mean total Physical Activity Scale for the Elderly score was 160 (SD 72), higher than described in healthy sedentary adults. The median daily step count was 7237 steps (IQR 5353, 10,038) and mean 6-minute walk distance was 545 m (SD 92). Median grip strengths were within predicted normal range, with an elevated median percentage body fat and low skeletal muscle mass found on body composition., Conclusion: Almost a quarter of International Lung Screen Trial participants assessed reported low levels of PA and have a potentially modifiable risk factor to improve health outcomes. Larger studies are needed to characterize the burden of inactivity among high-risk lung cancer screening populations., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Background & Aims: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with varying levels of liver tumor initiating or cancer stem cells in the tumors. We aimed to investigate the expression of different liver cancer stem cell (LCSC) markers in human HCCs and identify their regulatory mechanisms in stemness-related cells., Methods: We used an unbiased, single-marker sorting approach by flow cytometry, fluorescence-activated cell sorting, and transcriptomic analyses on HCC patients' resected specimens. Knockdown approach was used, and relevant functional assays were conducted on the identified targets of interest., Results: Flow cytometry on a total of 60 HCC resected specimens showed significant heterogeneity in the expression of LCSC markers, with CD24, CD13, and EpCAM mainly contributing to this heterogeneity. Concomitant expression of CD24, CD13, and EpCAM was detected in 32 HCC samples, and this was associated with advanced tumor stages. Transcriptomic sequencing on the HCC cells sorted for these individual markers identified epidermal growth factor receptor kinase substrate 8-like protein 3 (EPS8L3) as a common gene associated with the 3 markers and was functionally validated in HCC cells. Knocking down EPS8L3 suppressed the expression of all 3 markers. To search for the upstream regulation of EPS8L3, we found SP1 bound to EPS8L3 promoter to drive EPS8L3 expression. Furthermore, using Akt inhibitor MK2206, we showed that Akt signaling-driven SP1 drove the expression of the 3 LCSC markers., Conclusions: Our findings suggest that Akt signaling-driven SP1 promotes EPS8L3 expression, which is critical in maintaining the downstream expression of CD24, CD13, and EpCAM. The findings provide insight into potential LCSC-targeting therapeutic strategies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Compare accuracy of vertebral Hounsfield Unit (VHU) attenuation and FRAX and Garvan Fracture Risk Calculators in identifying low bone mineral density (BMD) and prevalent vertebral compression fractures (VF) in lung cancer screening (LCS) participants., Methods: Baseline CT scans from a single site of the International Lung Screen Trial were analysed. BMD was measured using VHU (of the most caudally imaged vertebra) and quantitative CT (QCT) (low BMD defined as <110 HU and <120 mg/cm 3, respectively). Prevalent VF were classified semi-quantitatively. 10-year FRAX and Garvan fracture risks were calculated using dual energy X-ray absorptiometry (DXA) femoral neck T-score where available. Discrimination was assessed by area under receiver-operating characteristic curves (AUC)., Results: 535 LCS participants were included; 41% had low VHU-BMD, 56% had low QCT-BMD and 10% had ≥1 VF with ≥25% vertebral height loss. VHU demonstrated 94% specificity and 70% sensitivity in identifying low QCT-BMD. VHU was superior to fracture risk tools in discriminating low QCT-BMD (AUC: VHU 0.94 vs FRAX 0.67, Garvan 0.64 [ p < 0.05]). In 64 participants with recent DXA scans, VHU was superior to FRAX T-score and Garvan T-score in discriminating low QCT-BMD (AUC: VHU 0.99, FRAX T-score 0.71, Garvan T-score 0.71 [ p < 0.05]). VHU was non-inferior to FRAX T-score and Garvan T-score in discriminating VF (AUC: VHU 0.65, FRAX T-score 0.53, Garvan T-score 0.61)., Conclusions: VHU outperforms clinical risk calculators in detecting low BMD and discriminates prevalent VF equally well as risk calculators with T-scores, yet is significantly simpler to perform., Advances in Knowledge: VHU measurement could aid osteoporosis assessment in high-risk smokers undergoing LCS.

Background and Aims: Understanding the mechanisms of HCC progression and metastasis is crucial to improve early diagnosis and treatment. This study aimed to identify key molecular targets involved in HCC metastasis., Approach and Results: Using whole-transcriptome sequencing of patients' HCCs, we identified and validated midline 1 interacting protein 1 (MID1IP1) as one of the most significantly upregulated genes in metastatic HCCs, suggesting its potential role in HCC metastasis. Clinicopathological correlation demonstrated that MID1IP1 upregulation significantly correlated with more aggressive tumor phenotypes and poorer patient overall survival rates. Functionally, overexpression of MID1IP1 significantly promoted the migratory and invasive abilities and enhanced the sphere-forming ability and expression of cancer stemness-related genes of HCC cells, whereas its stable knockdown abrogated these effects. Perturbation of MID1IP1 led to significant tumor shrinkage and reduced pulmonary metastases in an orthotopic liver injection mouse model and reduced pulmonary metastases in a tail-vein injection model in vivo . Mechanistically, SP1 transcriptional factor was found to be an upstream driver of MID1IP1 transcription. Furthermore, transcriptomic sequencing on MID1IP1-overexpressing HCC cells identified FOS-like 1 (FRA1) as a critical downstream mediator of MID1IP1. MID1IP1 upregulated FRA1 to subsequently promote its transcriptional activity and extracellular matrix degradation activity of matrix metalloproteinase MMP9, while knockdown of FRA1 effectively abolished the MID1IP1-induced migratory and invasive abilities., Conclusions: Our study identified MID1IP1 as a regulator in promoting FRA1-mediated-MMP9 signaling and demonstrated its role in HCC metastasis. Targeting MID1IP1-mediated FRA1 pathway may serve as a potential therapeutic strategy against HCC progression., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Objective: Since 2016, new therapies have transformed the standard of care for lung cancer, creating a need for up-to-date evidence for health economic modelling. We developed a discrete event simulation of advanced lung cancer treatment to provide estimates of survival outcomes and healthcare costs in the Australian setting that can be updated as new therapies are introduced., Methods: Treatment for advanced lung cancer was modelled under a clinician-specified treatment algorithm for Australia in 2022. Prevalence of lung cancer subpopulations was extracted from cBioPortal and the Sax Institute's 45 and Up Study, a large prospective cohort linked to cancer registrations. All costs were from the health system perspective for the year 2020. Pharmaceutical and molecular diagnostic costs were obtained from public reimbursement fees, while other healthcare costs were obtained from health system costs in the 45 and Up Study. Treatment efficacy was obtained from clinical trials and observational study data. Costs and survival were modelled over a 10-year horizon. Uncertainty intervals were generated with probabilistic sensitivity analyses. Overall survival predictions were validated against real-world studies., Results: Under the 2022 treatment algorithm, estimated mean survival and costs for advanced lung cancer 10 years post-diagnosis were 16.4 months (95% uncertainty interval [UI]: 14.7-18.1) and AU$116,069 (95% UI: $107,378-$124,933). Survival and costs were higher assuming optimal treatment utilisation rates (20.5 months, 95% UI: 19.1-22.5; $154,299, 95% UI: $146,499-$161,591). The model performed well in validation, with good agreement between predicted and observed survival in real-world studies., Conclusions: Survival improvements for advanced lung cancer have been accompanied by growing treatment costs. The estimates reported here can be used for budget planning and economic evaluations of interventions across the spectrum of cancer control., (© 2023. The Author(s).)

Background and Objective: Lung cancer is the leading cause of cancer-related mortality worldwide, partially attributed to late-stage diagnoses. In order to mitigate this, lung cancer screening (LCS) of high-risk patients is performed using low dose computed tomography (CT) scans, however this method is burdened by high false-positive rates and radiation exposure for patients. Further, screening programs focus on individuals with heavy smoking histories, and as such, never-smokers who may otherwise be at risk of lung cancer are often overlooked. To resolve these limitations, biomarkers have been posited as potential supplements or replacements to low-dose CT, and as such, a large body of research in this area has been produced. However, comparatively little information exists on their clinical efficacy and how this compares to current LCS strategies., Methods: Here we conduct a search and narrative review of current literature surrounding biomarkers of lung cancer to supplement LCS, and biomarkers of lung cancer in never-smokers (LCINS)., Key Content and Findings: Many potential biomarkers of lung cancer have been identified with varying levels of sensitivity, specificity, clinical efficacy, and supporting evidence. Of the markers identified, multi-target panels of circulating microRNAs, lipids, and metabolites are likely the most clinically efficacious markers to aid current screening programs, as these provide the highest sensitivity and specificity for lung cancer detection. However, circulating lipid and metabolite levels are known to vary in numerous systemic pathologies, highlighting the need for further validation in large cohort randomised studies., Conclusions: Lung cancer biomarkers is a fast-expanding area of research and numerous biomarkers with potential clinical applications have been identified. However, in all cases the level of evidence supporting clinical efficacy is not yet at a level at which it can be translated to clinical practice. The priority now should be to validate existing candidate markers in appropriate clinical contexts and work to integrating these into clinical practice., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-291/coif). KMF serves as an unpaid editorial board member of Translational Lung Cancer Research from August 2023 to July 2025. KMF has received competitive Research Grant Funding from MRFF and NHMRC in the past 36 months, honoraria or royalties from UpToDate and Cochrane Clinical Answers, travel support funding from WCLC, ATS, PCCP, and in kind equipment funding from Olympus and Mevis Veolity. KMF is the Former President of the Asia Pacific Society of Respirology. The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Pleural effusion occurs in both benign and malignant pleural disease. In malignant pleural effusions, the diagnostic accuracy and sensitivity of pleural fluid cytology is less than perfect, particularly for the diagnosis of malignant pleural mesothelioma, but also in some cases for the diagnosis of metastatic pleural malignancy with primary cancer in the lung, breast or other sites. Extracellular vesicles (EVs) carry an enriched cargo of microRNAs (miRNAs) which are selectively packaged and differentially expressed in pleural disease states. To investigate the diagnostic potential of miRNA cargo in pleural fluid extracellular vesicles (PFEVs), we evaluated methods for isolating the extracellular vesicle (EV) fraction including combinations of ultracentrifugation, size-exclusion chromatography (SEC) and ultrafiltration (10 kDa filter unit). PFEVs were characterized by total and EV-associated protein, nanoparticle tracking analysis and visualisation by transmission electron microscopy. miRNA expression was analyzed by Nanostring nCounter® in separate EV fractions isolated from pleural fluid with or without additional RNA purification by ultrafiltration (3 kDa filter unit). Optimal PFEV yield, purity and miRNA expression were observed when PFEV were isolated from a larger volume of pleural fluid processed through combined ultracentrifugation and SEC techniques. Purification of total RNA by ultrafiltration further enhanced the detectability of PFEV miRNAs. This study demonstrates the feasibility of isolating PFEVs, and the potential to examine PFEV miRNA cargo using Nanostring technology to discover disease biomarkers., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Journal of Extracellular Biology published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Lung cancer is the leading cause of cancer-related deaths. Early detection and diagnosis are critical, as survival decreases with advanced stages. Approximately 1.6 million nodules are incidentally detected every year on chest CT scan images in the United States. This number of nodules identified is likely much larger after accounting for screening-detected nodules. Most of these nodules, whether incidentally or screening detected, are benign. Despite this, many patients undergo unnecessary invasive procedures to rule out cancer because our current stratification approaches are suboptimal, particularly for intermediate probability nodules. Thus, noninvasive strategies are urgently needed. Biomarkers have been developed to assist through the continuum of lung cancer care and include blood protein-based biomarkers, liquid biopsies, quantitative imaging analysis (radiomics), exhaled volatile organic compounds, and bronchial or nasal epithelium genomic classifiers, among others. Although many biomarkers have been developed, few have been integrated into clinical practice as they lack clinical utility studies showing improved patient-centered outcomes. Rapid technologic advances and large network collaborative efforts will continue to drive the discovery and validation of many novel biomarkers. Ultimately, however, randomized clinical utility studies showing improved patient outcomes will be required to bring biomarkers into clinical practice., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Lung cancer screening in high-risk populations with low-dose computed tomography is supported by international associations and recommendations. Overdiagnosis is considered a risk of screening with associated harms. The aim of this paper is to determine the prevalence of subclinical lung cancer diagnosed post-mortem to better understand the reservoir of subclinical lung cancer., Methods: We searched EMBASE, PubMed, and MEDLINE databases from inception until March 2022 with no language restrictions. We considered all studies with ≥100 autopsies in adults. Two reviewers independently assessed eligibility of studies, extracted data, and assessed risk of bias of included studies. We performed a meta-analysis using a random-effects model for prevalence of subclinical lung cancer diagnosed post-mortem with sensitivity and subgroup analyses., Results: A total of 13 studies with 16 730 autopsies were included. Pooled prevalence was 0.4% (95% CI 0.20 to 0.82%, I 2  = 84%, tau 2  = 1.19, low certainty evidence,16 730 autopsies). We performed a sensitivity analysis excluding studies which did not specify exclusion of children in their cohort, with a pooled prevalence of subclinical lung cancer of 0.87% (95% CI 0.48 to 1.57%, I 2  = 71%, tau 2  = 0.38, 6998 autopsies, 8 studies)., Conclusions: This is the first published systematic review to evaluate the prevalence of post-mortem subclinical lung cancer. Compared to autopsy systematic reviews in breast, prostate and thyroid cancers, the pooled prevalence is lower in lung cancer for subclinical cancer. This result should be interpreted with caution due to the included studies risk of bias and heterogeneity, with further high-quality studies required in target screening populations., (© 2023. BioMed Central Ltd., part of Springer Nature.)